Starch derivatives, starch active substance conjugates, method for the production thereof and their use as medicaments

ABSTRACT

The invention relates to starch derivatives of formula (I), in which: X represents a bromine or iodine atom; R″ represents a straight-chain or branched alkyl group, aryl group or aralkyl group, and; R—CO— represents an oxidized substituted or unsubstituted starch radical that is oxidized on the reducing terminal group to form a carboxylic acid. Starch derivatives of formula (I) can selectively couple to active substances containing SH groups and have a prolonged half-life period in the human body. The invention also relates to coupling products of compound (I) with active substances, to methods for the production thereof, and to their use as medicaments

RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationNo. PCT/EP03/01716, filed Feb. 20, 2003, and published in German, whichclaims the benefit of German Application No. 102 07 072.5, filed Feb.20, 2002.

The present invention relates to starch derivatives, conjugates of suchstarch derivatives with active substances and a method for theirpreparation. The invention further relates to the use ofstarch/active-substance conjugates as drugs.

The conjugation of pharmaceutical active substances such as therapeuticproteins, antibiotics, nucleic acids, cytokines and hormones withpolyethylene glycol derivatives (“pegylation”) is a widely used method(Francis G. E. et al., Polyethylene glycol modification in tumourtargeting and cytokine therapy, J. Drug Targeting (1995), 3: 321-340).Active substances that are in themselves water-insoluble, for example,are thus converted into soluble derivatives, which can then beadministered into the blood stream.

Furthermore, it is possible to the molecular weight of active substancesby the coupling of polyethylene glycol derivatives in such a way thatfiltration via the kidneys is no longer possible, i.e. that theso-called kidney barrier is overcome and the half-life periods of suchderivatives is thus lengthened considerably compared with theunconjugated active substances. Moreover, as a result of the couplingwith polyethylene glycol derivatives, it is possible to reduce theantigenicity of, for example, proteins of non-human origin, which wouldotherwise lead to immunological side-effects when administered.

Polyethylene glycol (PEG) has the drawback, however, that it is anon-metabolisable molecule and proteins derivatised therewith can leadto vacuolisation of the kidneys. It is therefore of particular interestto carry out derivatisations of active substances with metabolisablepolymers, whose decomposition in the body can preferably be controlled.A suitable molecule for this is hydroxyethyl starch (HES), which haslong been widely used as a plasma expander in various molecularspecifications (DE 196 28 705 A1).

Even when administered in very high doses, HES exhibits side-effectsonly rarely and to a very small extent compared to with other plasmaexpanders, such as for example gelatin derivatives or dextranes, or alsohuman albumin.

A further unsolved problem with the derivatisation of active substances,however, is the selective binding of the active substance to thecarrier. In the case of proteins, it is for example desirable to carryout the coupling to a carrier at a sufficient distance from the reactivecentre or from the receptor. Otherwise, the activity may be reduced ordestroyed.

DE 196 28 705 A1 describes a method for binding haemoglobin tohydroxyethyl starch. However, the binding takes place relativelyunselectively via the numerous free amino groups of the haemoglobin.

In view of the discussed prior art, the problem underlying the inventionwas to make starch derivatives available that bind as selectively aspossible to an active substance.

Furthermore, such a starch derivative should be constituted so that asquantitative a binding as possible of an active substance takes place bycovalent binding to this starch derivative.

The problem underlying the invention was also to make starch derivativesavailable whose decomposition behaviour can be controlled in theorganism. In particular, the starch derivatives should be constitutedsuch that they cannot pass the kidney barrier and a rapid secretion isprevented. As a result, the starch derivatives should exhibit anextended half-life period in the blood serum. However, the starchderivatives should be decomposable without residue within aphysiologically reasonable period.

The solubility behaviour of active substances in aqueous phase and inorganic solvents should also be able to be controlled within a widerange by their binding to the known starch derivatives.

Finally, the problem underlying the invention was to make available amethod that is as simple and cost-effective as possible for thepreparation of such starch derivatives and their coupling products withactive substances.

These problems, as well as others which, though not mentioned literally,can however be deduced as self-evident from the correlations discussedherein or necessarily emerge therefrom, are solved with the starchderivatives described in claim 1. Expedient modifications of thesestarch derivatives according to the are protected in sub-claims 2-9related back to claim 1. The conjugates of such starch derivatives withactive substances are protected in claims 10-25.

With regard to a method for the preparation of starch/active substanceconjugates with which the stated starch derivatives are obtained as anintermediate product, claims 26-28 provide a solution to the underlyingproblem.

Claims 29-31 describe drugs which include the starch/active-substanceconjugates according to the invention and preferred medical applicationsof these drugs.

Through the preparation of compounds of the formula (I)

whereby X denotes a bromine or iodatome, R″ denotes a straight-chainedor branched alkyl, aryl or aralkyl compound R—CO— denotes an oxidisedsubstituted or unsubstituted starch radical, which is oxidised at thereducing end group to form a carboxylic acid, it is possible to makestarch derivatives available that bind extremely selectively to the SHfunctions of active substances.

The following advantages are also obtained with the compound accordingto the invention:

The special formulation of the starch derivatives prevents the latterfrom being able to pass the kidney barrier, as a result of which thehalf-life period of the active substance in the blood serum is extended.The half-life period describes the time after which half of the activesubstance used has been decomposed or secreted.

The compounds of formula (I) are decomposable without residue within aphysiologically reasonable period, but on the other hand exhibit acontrollable elimination behaviour.

Derivatives according to claim 1 can generally be prepared from anystarch that has a group oxidisable into a carboxylic acid. Preferably,it is the reducing end group of a starch. It has been found that theaforementioned properties of the compound (I) can be particularlyreadily achieved when the oxidised starch radical R—CO— is ahydroxyethyl starch radical.

Starting products for obtaining hydroxyethyl starch are starches whichhave a high content of amylopectin, the highly branched component ofstarch, in particular potato starch, wax-maize starch, sorghum starch orwax-like rice starch.

These starches are subjected to a hydrolytic decomposition reaction forthe rough pre-adjustment of the intended molecular weight. The molecularweight is reduced from approx. 20,000,000 Dalton to several millionDalton.

In the subsequent alkaline hydroxyethylation with knownhydroxyethylation agents, the introduction of a hydroxyethyl group intoposition 2, 3 and 6 of the anhydroglucose unit is possible.Disubstituted units, such as 2,3-dihydroxyethylene hydroglucose,2,6-dihydroxyethylene hydroglucose, are formed with less likelihood inthe synthesis.

Two differently defined substitution degrees exist to cover thesubstitution by hydroxyethyl groups.

The substitution degree MS (molar substitution) is defined as theaverage number of hydroxyethyl groups per anhydroglucose unit. It isdetermined from the total number of hydroxyethyl groups in a sample, forexample according to Morgan, by ether separation and subsequentquantitative determination of ethyliodide and ethylene, which arethereby formed.

On the other hand, the substitution degree DS (degree of substitution)is defined as the proportion of substituted anhydroglucose units of allanhydroglucose units. It can be determined from the measured quantity ofunsubstituted glucose after hydrolysis of a sample. It emerges fromthese definitions that MS>DS. In the case where monosubstitution ispresent, i.e. each substituted anhydroglucose unit carries only onehydroxyethyl group, MS=DS.

A hydroxyethyl starch radical within the formula (I) of the presentinvention preferably has a substitution degree MS of 0.1 to 0.8.Particularly preferably, the hydroxyethyl starch radical has asubstitution degree MS of 0.4 to 0.7.

The reactivity of the individual hydroxyethyl groups in theunsubstituted anhydroglucose unit with respect to hydroxyethylation isdifferent depending on the reaction conditions. Within certain limits,the substitution sample, i.e. the individual, differently substitutedanhydroglucoses which are statistically distributed over the individualpolymer molecules, can be influenced by this. To advantage, the C₂- andthe C₅-position are predominantly hydoxyethylated, whereby theC₆-position is substituted more frequently on account of its easieraccessibility.

Within the scope of this invention, used is preferably made ofhydroxyethyl starches (HES) substituted predominantly in the C₂position, which are substituted as homogeneously as possible. Thepreparation of such HES is described in EP 0 402724 B2. They aredecomposable without residue within a physiologically reasonable period,but on the other hand exhibit a controllable elimination behaviour. Thepredominant C₂ substitution makes the hydroxyethyl starch relativelydifficultly decomposable for α-amylase. It is advantageous, if possible,for no anhydroglucose units substituted one after the other inside thepolymer molecule to occur, in order to guarantee decomposability withoutresidue. Furthermore, despite the low substitution, such hydroxyethylstarches possess a sufficiently high solubility in aqueous medium, sothat the solutions are stable even over lengthier periods and noagglomerates or gels are formed.

Relaxed to the hydroxyethyl groups of the anhydroglucose units, ahydroxyethyl starch radical within the formula (I) of the presentinvention preferably has a ratio of C₂:C₆ substitution in the range from2 to 12. Particularly preferably, the ratio of C₂:C₆ substitutionamounts 3 to 11.

For the coupling with an active substance, hydroxyethyl starches (HES)are oxidised preferably at their reducing end into carboxylic acid orlactone. DE 196 28 705 A1 describes a method in which HES is oxidisedwith iodine/potassium hydroxide at the reducing end. Subsequent couplingto an active substance can take place via the acid function obtained.

The radical R—CO— in the compound of formula (I) according to theinvention denotes in the preferred formula on an oxidised hydroxyethylstarch radical, which is oxidised at the reducing end group in themanner described to form a carboxylic acid.

Due to the use of the natural starting raw material amylopectin and alsodue to the method of preparation, in which separation of the polymerchains is necessary to a certain extent, hydroxyethyl starch is notpresent as a molecular-uniform substance a defined molecular weight, butas a mixture of molecules of differing size, which are also substitutedvariously by hydroxyethyl groups. The characterisation of such mixturesrequires the use of statistically averaged magnitudes (see K.Sommermeyer et al., “Klinisch verwendete Hydroxyethylstärke:Physikalisch-chemische Charakterisierung” 271 (1987)). In order todenote the average molecular weight, therefore, the averaged molecularweight Mw is used. The general definition of this average value reads asfollows:

$M_{w} = \frac{\sum\limits_{i}{N_{i}\mspace{11mu}\bullet\mspace{11mu} M_{i}^{w}}}{\sum\limits_{i}{N_{i}\mspace{11mu}\bullet\mspace{11mu} M_{i}^{w - 1}}}$

A hydroxyethyl starch radical R—CO— within the formula (I) of thepresent invention preferably has an average molecular weight Mw of 2000to 1,000,000 D (determined with gel permeation chromatography). Stillmore preferably, the average molecular weight Mw amounts to 5,000 to500,000 D and most preferably to 8,000 to 250,000 D.

The group R″ in the compound (I) can contain both saturated as well asunsated bonds. An alkyl, aryl or aralkyl radical as R″ can also containfurther substituents, such as for example alkyl, aryl, aralkyl, halogen,carbonyl, acyl, carboxyl, carboxylester, hydroxy, thiol, alkoxy and/oralkylthio substituents. In a preferred form of embodiment, R″ is a groupof the formula (CH₂)_(n), whereby n denotes a whole number from 1 to 10.Particularly preferably, R″ is an ethylene, propylene, butylene,pentamethylene, hexamethylene or octamethylene group.

The invention also relates to starch/active-substance conjugates of thegeneral formula (II)

whereby R″ denotes a straight-chained or branched alkyl, aryl or aralkylgroup, R—CO— denotes an oxidised substituted or unsubstituted starchradical, which is oxidised at the reducing end group to form carboxylicacid, and R′ is the radical of an active substance.

The starch/active-substance conjugates of formula (II) are couplingproducts from the previously described compounds of the formula (I) andan active substance, which contains at least one SH group. The radicalsR—CO— and R″ have the same significance as already explained previouslywith the aid of formula (I).

Preferred active substances R′—SH, which are contained as the radicalR′—S— in the compounds of the formula (II), are selected from a peptide,a protein, an antibiotic, a nucleic acid, or a hormone. The prerequisiteis that these compounds contain at least one SH group.

It can also be a protein or peptide to which a cysteine radical has beenintroduced by targeted mutagenesis. Inasmuch as no SH groups are presentin proteins or peptides, it is possible within the scope of the presentinvention to use so-called cysteine-muteines of therapeutic proteins,with which an exchange or an introduction of cysteine radicals has beenbe carried out selectively by targeted mutagenesis using geneticengineering. Such an exchange is known among experts and is described,amongst others, in: A. Bendele et al., Short Communication: RenalTubular Vacuolation in Animals Treated with Polyethylene-Glycolconjugated Proteins, Toxicological Sciences 42, 152-157 (1998).

SH functions can also be introduced into active substances carrying aprimary amino group by conversion with 2-iminothiolane (Trauts reagent),before the active substances are reacted with compounds of the formula(I). The introduction of SH functions by this method into activesubstances, such as for example into proteins, is generally knownamongst experts.

Therapeutic antibodies, antibody fab fragments and antibody F(ab′)₂fragments are preferred active-substance proteins. On account of theirrelatively low molecular weight, such antibody fragments are easilypassable through the kidneys and can be extended in their serumhalf-life period by derivatisation with starch. It has also beenestablished within the scope of the present invention that thehydrolytic decomposition of the antibodies or antibody fragments byproteases can be reduced with the aid of derivatisation withhydroxyethyl starch.

In further preferred forms of embodiment, the active substance is acytokine, in particular an interferon α 2a or an interferon α 2b, orerytropoetin.

Within the scope of the present invention, it has been established thatthe solubility of an active substance in aqueous medium can beinfluenced when the latter is coupled to a compound of the formula (I)and converted into a starch/active-substance conjugate of the formula(II).

Within the scope of the invention, it has also been established that thesolubility of a protein or enzyme in organic solvents can be increasedwhen the protein or enzyme is coupled to a compound of the formula (I)and converted into a starch/active-substance conjugate of the formula(II). Dimethyl formamide, dimethyl sulphoxide or dimethyl acetamide arepreferred aprotic solvents.

The present invention also relates in a further aspect to a method forthe preparation of the previously describe starch/active-substanceconjugates of the formula (II). The initially described starchderivative of the formula (I) is obtained as an intermediate product ofthis method. The method is characterised by the following steps:

-   a) The reducing end groups of a substituted or unsubstituted starch    are first selectively oxidised to form the carboxyl or lactone    group. Hydroxyethyl starch is preferably used. The oxidation can    take place for example with iodine/potassium hydroxide according to    DE 196 28 705 A1.-   b) The oxidised starch or hydroxyethyl starch obtained in step a) is    reacted at its carboxylic group or lactone group with a diamine.    H₂N—R″—NH₂,    whereby R″ denotes an alkyl, aryl or aralkyl radical, which can be    branched or unbranched. The stated radicals can also contain    saturated as well as unsaturated bonds. An alkyl radical, aryl    radical or aralkyl radical can also contain further substituents,    such as for example alkyl, aryl, aralkyl, halogen, carbonyl, acyl,    carboxyl, carboxyl, carboxylester, hydroxy, thiol, alkoxy and/or    alkylthio substituents.

Preferably, R″ is an unbranched saturated alkyl radical (CH₂)_(n),whereby n denotes a whole number from 2 to 10. Particularly preferredcompounds are ethylene diamine, 1,3-diaminopropane, 1,4-diaminobutane,1,5-diaminopentane, 1,6-daminohexane and 1,8-diaminooctane.

By reacting the oxidised substituted or unsubstituted starch with thediamine described above, a compound of the formula (III)

is obtained, in which R—CO— represents an oxidised substituted orunsubstituted starch radical, as already described at the outset withthe aid of the formula (I), said starch radical being oxidised at thereducing end group to form a carboxylic acid.

-   c) The compound of the formula (III) is reacted with a halogen    acetic and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as an    activator to form a compound of the formula (I)

in which X denotes a bromine or iodatome.

-   d) Finally, the compound of the formula (I) is reacted with an    active substance with at least one thiol radical R′—SH to form a    starch/active-substance conjugate of the general formula (II)

whereby R′ represents an active-substance radical.

It has been found that, under neutral to slightly alkaline conditions,the thiol group of an active substance reacts more rapidly than otherreactive groups with compounds of the formula (I). Preferably, the pHvalue amounts to 6.5-8.5. Under these conditions, deprotonisation of thethiol group takes place to thiolation, which is particularly reactiveand reacts selectively with compounds of the formula (I).

It has been established that the derivatisation of an active substanceby coupling to a starch can be carried out extremely selectively withthe method described above. Selective means in this case that an activesubstance essentially reacts solely via its thiol groups with compoundsof the formula (I) and that the coupling to the starch/active-substanceconjugate essentially takes place solely via thiol ether bonds.

Particularly preferably, the coupling method is carried out withpeptides or proteins containing SH groups. A reaction of the compound(I) is also possible with SS groups of a protein or peptide, after thelatter have been converted into SH groups.

The yields of the reaction of compounds of the formula (I) with apeptide or protein containing SH groups amounts, depending on themolecular weight of the protein or peptide and the number of SH or SSgroups, to between 20% and 90%. In the favourable case, therefore, alargely quantitative coupling of an active substance to the starchcarrier can be achieved.

It is also possible to react an intermediate product of the formula(III) in step c) of the method described above with other commonly usedcross-inking agents instead of with a halogen acetic acid. In this case,a functional group of the cross-linking agent reacts with the primaryamino group of the compound (III). In the following step, one of theremaining functional groups of the cross-linking agent reacts with afunctional group of an active substance, preferably with an SH group, asa result of which a starch/active-substance conjugate is formed.Commonly used cross-linking agents are, for example, bifunctionalcross-linking agents with α-ω-terminal identical or different functionalgroups. An overview of such cross-linking agents can be found in thecatalogue from the in Perbio (2001/2002).

Furthermore, it is possible, and self-evident to the expert, to react astarch radical or hydroxyethyl starch radical described at the outset,which is oxidised at the reducing end group to form a carboxylic acid,directly with one of the commonly used cross-linking agents describedabove. In this case, a functional group of the cross-linking agentreacts with the carboxyl group of the oxidised starch or hydroxyethylstarch. In the following step, one of the remaining functional groups ofthe cross-lining agent reacts with a functional group of an activesubstance, preferably with an SH group, as a result of which astarch/active-substance conjugate is formed

According to one aspect of the present invention, the starch derivativesof active substances described above are used for the preparation of adrug. Preferably, it is a drug for the treatment of infectious diseasesor hormonal disturbances. In this connection, such a drug can containstandard pharmaceutical accessory agents.

The invention is described below with an ample, although the inventionis not intended to be restricted thereto.

EXAMPLE 1

10 g of conjugate of oxidised hydroxyethyl starch with a mean molecularweight Mw of 40,000 and a substitution degree MS of 0.2, preparedanalogous to DE 196 28 705 A1, was dissolved together with ethylenediamine in 50 ml of distilled water. 0.2 g of bromoacetic acid wasdissolved in 5 ml of distilled water, the pH value was set at 4.5 with0.01 normal soda lye and this solution was added to theamino-functionalised hydroxyethyl starch described above. Whilststirring, 0.1 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide wasadded to the reaction mixture, and the pH value was held for an hour at4.5 by adding 0.01 normal hydrochloric acid and then 0.01 normal so lye.After a further 2 hours reaction time, the reaction product wasultra-filtered and then precipitated with ethanol and washed and driedwith light protection in a vacuum.

1. A starch derivative comprising formula (I):

wherein X is a bromine or iodatome; R″ is a straight-chained or branchedalkyl, aryl, or aralkyl group; and R—CO— is an oxidized substituted orunsubstituted starch radical, which is oxidized at the reducing endgroup to form a carboxylic acid.
 2. The starch derivative of claim 1,wherein R″ is a group of the formula (CH₂)_(n) and n denotes a wholenumber from 1 to
 10. 3. The starch derivative of claim 1, wherein theradical R—CO— is a hydroxyethyl starch radical oxidized to formcarboxylic acid, said hydroxyethyl starch radical having an averagemolecular weight of from 2,000 to 1,000,000 Daltons.
 4. The starchderivative of claim 3, wherein said hydroxyethyl starch radical has anaverage molecular weight of from 5,000 to 500,000 Daltons.
 5. The starchderivative of claim 4, wherein said hydroxyethyl starch radical has anaverage molecular weight of from 8,000 to 250,000 Daltons.
 6. The starchderivative of claim 1, wherein the radical R—CO— is a hydroxyethylstarch radical oxidized to form carboxylic acid, said hydroxyethylstarch radical having a substitution degree MS of from 0.1 to 0.8. 7.The starch derivative of claim 6, wherein said hydroxyethyl starchradical has a substitution degree MS of from 0.4 to 0.7.
 8. The starchderivative of claim 1, wherein the radical R—CO— is a hydroxyethylstarch radical oxidized to form carboxylic acid, said hydroxyethylstarch radical having a ratio of C₂:C₆ substitution in the range of from2-12 related to the hydroxyethyl groups of the anhydroglucose units. 9.The starch derivative of claim 8, wherein said hydroxyethyl starchradical has a ratio of C₂:C₆ substitution in the range of from 3-11related to the hydroxyethyl groups of the anhydroglucose units.
 10. Astarch/active-substance conjugate comprising formula (II)

wherein R″ denotes a straight-chained or branched alkyl, aryl, oraralkyl group; R—CO— denotes an oxidized substituted or unsubstitutedstarch radical, which is oxidized at the reducing end group to form acarboxylic acid; and R′ is the radical of an active substance.
 11. Thestarch/active-substance conjugate of claim 10, wherein R″ is a group ofthe formula (CH₂)_(n) and n denotes a whole number from 1 to
 10. 12. Thestarch/active-substance conjugate of claim 10, wherein the radical R—CO—is a hydroxyethyl starch radical oxidized to form carboxylic acid, saidhydroxyethyl starch radical having an average molecular weight of from2,000 to 1,000,000 Daltons.
 13. The starch/active-substance conjugate ofclaim 12, wherein said hydroxyethyl starch radical has an averagemolecular weight of from 5,000 to 500,000 Daltons.
 14. Thestarch/active-substance conjugate of claim 13, wherein said hydroxyethylstarch radical has an average molecular weight of from 8,000 to 250,000Daltons.
 15. The starch/active-substance conjugate of claim 10, whereinthe radical R—CO— is a hydroxyethyl starch radical oxidized to formcarboxylic acid, said hydroxyethyl starch radical having a substitutiondegree MS of from 0.1 to 0.8.
 16. The starch/active-substance conjugateof claim 15, wherein said hydroxyethyl starch radical has a substitutiondegree MS of from 0.4 to 0.7.
 17. The starch/active-substance conjugateof claim 10, wherein the radical R—CO— is a hydroxyethyl starch radicaloxidized to form carboxylic acid, said hydroxyethyl starch radicalhaving a ratio of C₂:C₆ substitution in the range of from 2-12 relatedto the hydroxyethyl groups of the anhydroglucose units.
 18. Thestarch/active-substance conjugate of claim 17, wherein said hydroxyethylstarch radical has a ratio of C₂:C₆ substitution in the range of from3-11 related to the hydroxyethyl groups of the anhydroglucose units. 19.The starch/active-substance conjugate of claim 10, wherein the activesubstance is selected from a peptide, a protein, an antibiotic, anucleic acid, or a hormone.
 20. The starch/active-substance conjugate ofclaim 19, wherein the protein is an antibody, an antibody fab fragment,or an antibody F(ab′)₂ fragment.
 21. The starch/active-substanceconjugate of claim 19, wherein the protein is an erythropoetin.
 22. Thestarch/active-substance conjugate of claim 19, wherein the protein is apeptide or protein in which a cysteine radical has been inserted bytargeted mutagenesis.
 23. The starch/active-substance conjugate of claim19, wherein it concerns an active substance in which an SH function hasbeen inserted by reaction with 2-iminothiolane.
 24. Thestarch/active-substance conjugate of claim 19, wherein the activesubstance is a cytokine.
 25. The starch/active-substance conjugate ofclaim 24, wherein the cytokine is selected from interferon α 2a andinterferon α 2b.
 26. A method of preparing starch/active-substanceconjugates, the method comprising the steps of: a) oxidizing thereducing end groups of a substituted or unsubstituted starch to form acarboxyl or a lactone group; b) reacting the carboxyl group or thelactone group prepared in step a) with a diamine H2N—R″—NH2 to form acompound of formula (III)

wherein R″ is a straight-chained or branched alkyl, aryl, or aralkylgroup, and R—CO— is an oxidized substituted or unsubstituted starchradical, which is oxidized at the reducing end group to form acarboxylic acid; c) reacting the compound of formula (H) with a halogenacetic acid and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as anactivator to form a compound of formula (I):

wherein X is a bromine or iodatome; and d) reacting the compound offormula (I) with an active substance R′SH containing at least one SHgroup to form a starch/active-substance conjugate of general formula(II):

wherein R′ is an active-substance radical.
 27. The method of claim 26,wherein R″ is a group of the formula (CH₂)_(n) and n is a whole numberfrom 1 to
 10. 28. The method of claim 26, wherein the reaction of stepd) is carried out at a pH value of between 6.5 and 8.5.
 29. Apharmaceutical compound, comprising a carrier or diluent and astarch/active-substance conjugate of general formula (II)

wherein R″ denotes a straight-chained or branched alkyl, aryl, oraralkyl group; R—CO— denotes an oxidized substituted or unsubstitutedstarch radical, which is oxidized at the reducing end group to form acarboxylic acid; and R′ is the radical of an active substance.